Continuity in Methylphenidate Treatment of Adults With Attention-Deficit/Hyperactivity Disorder

BACKGROUND: Although stimulant therapy is commonly discontinued early in adults with attention-deficit/hyperactivity disorder (ADHD), the factors that contribute to continuity of stimulant therapy remain largely unknown. OBJECTIVES: To (1) compare the continuity of methylphenidate (MPH) therapy among adults who use immediate-release methylphenidate (IR-MPH) for ADHD with adults who use extended-release methylphenidate (ER-MPH) formulations, and (2) examine some of the methodological issues involved in research with administrative claims for ADHD. METHODS: An analysis of pharmacy and medical claims for 75 US managed care plans representing approximately 55 million beneficiaries for dates of service from January 1, 2000 through December 31, 2004. Patients had to be adults (aged 18 to 64 years) who had 1 or more outpatient medical claims for ADHD (International Classification of Diseases, Ninth Revision, Clinical Modification code 314.xx) during the study period and who had initiated ER-MPH or IR-MPH treatment for ADHD. The study cohorts did not have a pharmacy claim for MPHs, amphetamines, pemoline, or atomoxetine for 6 months preceding the first (index) MPH pharmacy claim. Stimulant treatment episodes were defined to start on the index date and terminate on the last date supplied of the index medication. Episodes of treatment were also defined as terminated if there was a gap of e30 days between the end of the days supplied on the pharmacy claim and the date of the next pharmacy claim for the index medication. RESULTS: Less than one third (30.0%) of the adult patients who were prescribed MPH had 1 or more medical claims with a diagnosis code for ADHD. For the adult MPH patients with at least 1 medical claim with a diagnosis code for ADHD, the patients who initiated therapy with ER-MPH (N=2,833) were significantly younger, were more likely to be male, and were less likely to be treated by a psychiatrist than were the patients who initiated therapy with IR-MPH (N=2,289). Only 50.5% (n=1,156) of IR-MPH patients and 61.4% (n=1,739) of ER-MPH patients had more than 1 pharmacy claim for the index MPH medication. Adults treated with ER-MPH also had a significantly longer median duration of treatment with the index medication (ER-MPH: 68 days, 95% confidence interval [CI], 65-71 days vs. IR-MPH 39 days, 95% CI, 33-52 days). Controlling for group differences in age, gender, treatment by a psychiatrist, recently prescribed psychotropic medications, treated mental disorders, emergency mental health treatment, and inpatient mental health care, ER-MPH initiation was associated with an average 27% longer duration of treatment than with IR-MPH (survival time ratio: 1.27, 95% CI, 1.20-1.35). CONCLUSIONS: In management of adult ADHD, use of ER-MPH formulations was associated with a longer median duration of the initially prescribed medication than was use of IR-MPH. It is unknown whether the observed absolute unadjusted difference of 29 days in median length of therapy is clinically important.


ReseaRch
What is already known about this subject What this study adds •O nly 30% of adult patients who received either immediaterelease MPH (IR-MPH) or extended-release MPH (ER-MPH) had amedical or facility claim with adiagnosis code for ADHD.
•F or patients who received MPH and had at least 1medical or facility claim with adiagnosis code for adiagnosis code for ADHD, ER-MPH had alonger median duration of therapy than did IR-MPH (68 days versus 39 days, respectively).
•P revious research indicates that episodes of treatment with stimulants such as methylphenidate (MPH) tend to be relatively brief in the community treatment of adult ADHD, with amean of 50 days of therapy.

Continuity in Methylphenidate Treatment of Adults
With Attention-Deficit/Hyperactivity Disorder adults initiating pharmacological treatment for ADHD continued their medications for an average of only 50 days. 13 Although early discontinuation of treatment commonly occurs in the care of adult ADHD, the factors that promote continuity of stimulant treatment remain largely unknown. Among youth with ADHD, extended-release methylphenidate (ER-MPH) formulations area ssociated with significantly greater treatment continuity than immediate-release formulations. 12,14 This higher rate of treatment continuity with ER-MPH may be related to the simpler dosing regimen in which asingle dose provides clinical effects for about 8h ours compared with IR-MPH, which requires several daily doses to provide coverage throughout the day. 15 In the present study,weevaluated whether ER-MPH formulations areassociated with greater treatment continuity than are IR-MPH formulations in the community management of adults with ADHD under managed care. We comparet he duration of MPH treatment episodes of adults from various US managed careh ealth plans, following initiation with either ER-MPH or IR-MPH formulations.
nn Methods

Source of Data
Analyses of medical service and pharmacy claims from the PharMetrics (2000-2004) database arep resented. This database contains standardized prescription, claims, and enrollment information from 75 managed careo rganizations that collectively cover moret han 55 million lives, 16 similar to the distribution of the US population by age and gender.Enrollment data include information on patient demographics and periods of eligibility for services. Claims data include diagnostic and provider information for all inpatient and outpatient services. Prescription claims include the name of the medication filled, the quantity of units dispensed, the days of supply,a nd the National Drug Code.
All study procedures werea pproved by the Institutional Review Boardofthe University of Pennsylvania.

Selection of Study Cohorts
Selected patients werebetween 18 and 64 years on the date of the first or index pharmacy claim for ER-MPH or IR-MPH. To assess patient characteristics beforethe index prescription and continuity of MPH after this prescription, the sample was limited to patients who werecontinuously enrolled in the health plan for 6months beforeand 12 months after the index MPH prescription. Because we wereinterested in new stimulant treatment episodes, patients who received any stimulant prescription during the 6m onths beforethe index MPH prescription wereexcluded from the analysis. The initial MPH claim was limited to am aximum of 90 days. To focus the analysis on patients receiving treatment for ADHD, we restricted the sample to adults who received 1ormore outpatient treatment claims for ADHD (  ). The group also included patients treated with morethan 1ER-MPH (n =68). In some analyses, the 4E R-MPH formulations werec ompared. All other selected patients wereassigned to the IR-MPH group.

Duration of MPH Treatment Episodes
Stimulant treatment episodes wered efined to start on the index date and terminate on the last date supplied of the index medication. Episodes of treatment werea lso defined as terminated if therew as ag ap of ≥ 30 days between the end of the days supplied on the pharmacy claim and the date of the next pharmacy claim for the index medication. 12 Each patient contributed only 1s timulant treatment episode to the analysis. Once-per-day dosing was assumed to occur when the number of units in the pharmacy claim matched the number of days in the days supply field.

Background Characteristics
Study patients werefi rst characterized with respect to patient age, gender,s pecialty of the prescribing physician (psychiatrist or other medical specialist treatment during the study period), and ADHD subtype. Three subtypes of ADHD wered efined on the basis of the largest number of relevant claims for each patient during the study period: (1) ADHD without hyperactivity (ICD-9-CM code 314.00), (2) ADHD with hyperactivity (code 314.01), and (3) other ADHD subtypes (other code: 314). Mental health claims during the 6m onths preceding the index MPH pharmacy claim wereu sed to classify patients as having received treatment for mood disorders (codes 296, 300.4, 311), substance use disorders (codes 291, 292, 303-305), anxiety disorders (codes 300.0, 300.2, 300.3, 308.3, 309.81), and a residual diverse group of all other mental disorders, except mental retardation (codes 290-316, except above).

Analytic Strategy
Patients treated with ER-MPH or IR-MPH werefi rst compared with respect to demographic and clinical background characteristics. Group comparisons arep resented with 95% confidence intervals (CIs).
The mean and median duration of MPH treatment were calculated for both study groups with surrounding 95% CIs. Cox accelerated failuret ime regressions based on the Weibull distribution werep erformed, controlling for patient age, gender,treating specialist, other treated mental disorders, claims for other prescribed psychotropic medications, and claims for emergency and inpatient services in which the first listed diagnosis was am ental disorder (ICD-9-CM codes 290-316).
Emergency department and inpatient service use wereidentified using Pharmetrics specified categories for place of service, procedurec odes (Current Procedural Terminology [CPT-4], HealthcareC ommon ProcedureC oding System [HCPS], and revenue codes. In these analyses, the dependent variable was time to discontinuation of the index MPH medication. When the resulting parameter estimate for drug group was exponentiated, the regression provided ar atio of time to discontinuation between groups or the survival time ratio (STR). The time to discontinuation of the index MPH medication was also examined with aKaplan-Meier survival curve, and the Wilcoxon test of equality over strata was used to comparethe curves.
We also compared the mean and median duration of MPH treatment episodes among 4s ubgroups of adult patients prescribed ER-MPH; those treated with OROS-MPH, MPH-LA, MPH-CD, or other extended-release MPH preparations. Separate  Table 1). As ignificantly larger percentage of the IR-MPH patients received treatment with anxiolytic and antidepressant medications during the 6m onths preceding the index MPH prescription (see Table 2). The two MPH groups did not differ significantly with respect to the proportion who received treatment for mood, anxiety,o rs ubstance use disorders or the proportion who received inpatient or emergency mental health treatment during the 6m onths beforet he index prescription (

Continuity of MPH Treatment
The overall median continuity of MPH treatment was significantly longer for patients treated with ER-MPH than with IR-MPH (Table 3). Only 50.5% (n =1 ,156) of IR-MPH patients and 61.4% (n =1 ,739) of ER-MPH patients had more than 1pharmacy claim for the index MPH. Adults treated with ER-MPH also had as ignificantly longer median duration of stimulant treatment (ER-MPH: 68 days, 95% CI, 65-71 days vs. IR-MPH: 39 days, 95% CI, 33-52 days). AKaplan-Meier curve revealed significantly greater time to index MPH discontinuation for patients treated with ER-MPH rather than IR-MPH (Wilcoxon 2 =7 7.7, df =1 , P <0.001; see Figure2 ). In am ultivariate analysis, which controlled for background demographic and clinical characteristics, ER-MPH patients had an estimated 27% (STR =1.27) longer duration of index MPH treatment than did IR-MPH patients (Table 4). In this multivariate analysis, the duration of MPH treatment was also significantly related to treatment by ap sychiatrist and treatment with an antidepressant medication or mood stabilizer prior to the index MPH prescription (Table 4). Mental health treatment in an emergency department during the 6months beforeinitiation of MPH therapy and younger age (18-35 years) wereeach significantly and independently related to ashorter duration of index MPH treatment ( Table 4). The generalized R 2 for this model was 0.061.
Among patients treated with ER-MPH preparations, those treated with OROS-MPH had the longest median duration of index stimulant treatment, followed by MPH-CD, MPH-LA, and the other ER-MPH group. The times to index MPH discontinuation of the 4extended-release groups aredisplayed in Figure3. The survival times of the 4curves significantly differ from each other (Wilcoxon 2 =49.1, df=3, P <0.001). Controlling for group differences in age, gender,t reatment by ap sychiatrist, recently prescribed psychotropic medications, treated mental disorders, emergency mental health treatment, and inpatient mental health care, OROS-MPH initiation was associated with an average 46% longer duration of treatment than was the other ER-MPH group  nn

Discussion
In this managed carep opulation, adults starting ER-MPH formulations for the treatment of ADHD had greater continuity of treatment with the initially prescribed medication than adults starting IR-MPH formulations had. After controlling for several basic demographic, clinical, and treatment characteristics, ER-MPH was associated with a2 7% longer duration of treatment than IR-MPH was, but the absolute difference was fewer than 30 days. The reasons for the difference in treatment continuity arenot known. It is possible that greater ease of administration associated with once-a-day dosing may help to account for the longer observed stimulant therapy episodes of patients treated with ER-MPH rather than with IR-MPH. Compared with once-a-day dosing, multiple daily doses may make patients morep rone to missed doses and consequent decline in treatment response. In the management of several medical conditions, morec omplex dosing regimens have been related to problems with treatment continuity and poorer clinical outcome. [18][19][20][21] At the same time, some patients and physicians may prefer IR-MPH because it allows for greater ease in dose titration and permits morefl exible dosing schedules that may minimize side effects. 22 Of the ER-MPH products, OROS-MPH had the longest treatment continuity.This finding extends similar results concerning the continuity of MPH treatment for children and adolescents. 12 Detailed clinical assessments, not available in administrative data, might help to reveal reasons for the differences in treatment duration among the ER-MPH formulations. It is possible that the greater treatment continuity of OROS-MPH compared with the other ER-MPH formulations is related to its longer half-life. Administration of OROS-MPH results in an immediate release of MPH, followed by as lower release of MPH over approximately 12 hours.
MPH-LA, MPH-CD, and the other extended-release preparations have somewhat faster release. After as ingle dose of MPH-LA, MPH is released over an 8-hour period. MPH-CD typically results in ap eak MPH plasma concentration approximately 1.5 hours after dosing, followed by asecond peak approximately 4.5 hours after dosing. 23 It is also possible that the differences in the continuity of the ER-MPH formulations are explained by differences in unmeasured patient or physician characteristics that have confounded associations between MPH formulation and treatment continuity.A lthough the model controlled for several covariates, the generalized R 2 of 6.1% indicates that 94% of the variance in treatment continuation is attributed to unmeasured confounding factors.
The observed differences in stimulant continuity among MPH preparations occurred against abackground of widespread early discontinuation of treatment. For both groups, the median duration of MPH treatment episodes was less than than 70 days. An important priority remains the identification of patient, treatment, and contextual factors that contribute to pervasive early MPH discontinuation. An understanding of the most common reasons for early discontinuation may provide a framework for developing effective interventions to reduce prematured iscontinuation of MPH treatment in adults with ADHD. It may be especially important to determine the extent to which early MPH treatment discontinuation reflects problems with medication tolerability or side effects, including sleep difficulties, reduced appetite, stomach ache, exacerbation of tic disorders, or cardiovascular concerns.

Limitations
First and foremost among the study limitations is the fact that the clinical significance of MPH discontinuation cannot be determined from the current analysis. Mores pecifically,i ti s not possible to distinguish clinically appropriate treatment discontinuation from prematuretreatment termination for cause, such as perceived lack of efficacy or adverse effects. Second, Days of MPH Treatment patients initially prescribed IR-MPH may differ from those initially prescribed ER-MPH in important unmeasured clinical or treatment characteristics that may place the IR-MPH group at increased risk of early MPH discontinuation. In av ariety of contexts, patient education, increased number of hours when the clinic is open, and improved communication between physicians and patients have been demonstrated to improve adherence to medication regimens. 25 Third, the present analysis was limited to patients treated with MPH rather than with mixed amphetamines, atomoxetine, or other medications commonly used to treat adult ADHD. Fourth, although pharmacy claims databases tend to be reliable and valid, [26][27] ap harmacy claim does not guarantee actual medication consumption. In addition, some patients may take medications without generating ac laim (e.g., out-of-pocket purchases), while other patients may take less than the amount prescribed. Fifth, because the study involved participants in private managed careplans, the results may not be generalizable to other patient populations, such as those insured by Medicaid or the Veterans Administration.

nn Conclusions
In this observational study of adults treated for ADHD, ER-MPH was associated with significantly longer treatment episodes than was IR-MPH. In 1s tudy of pediatric ADHD, patients who werea dherent with stimulants exhibited significantly greater symptom improvement at long-term follow-up than did patients who weren onadherent with stimulants. 24 An important challenge for futureresearch involves determining the effects of extending stimulant therapy continuity on key clinical and functional outcomes in the community treatment of adult ADHD.